A 12-week Treatment, Multi-center, Randomized, Double-blind, Parallel-group, Placebo and Active Controlled Study to Assess the Efficacy, Safety, and Tolerability of Indacaterol Maleate / Glycopyrronium Bromide in COPD Patients With Moderate to Severe Airflow Limitation

Chronic Obstructive Pulmonary Disease (COPD) Clinical Trial

Official title:

A 12-week Treatment, Multi-center, Randomized, Double-blind, Parallel-group, Placebo and Active Controlled Study to Assess the Efficacy, Safety, and Tolerability of Indacaterol Maleate / Glycopyrronium Bromide in COPD Patients With Moderate to Severe Airflow Limitation

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01712516
• Other study ID #: CQVA149A2337
• Status: Completed
• Phase: Phase 3
• First received: October 19, 2012
• Last updated: July 13, 2015
• Start date: December 2012
• Est. completion date: February 2014

Study information

• Verified date: July 2015
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This study will assess the efficacy, safety and tolerability of indacaterol maleate/glycopyrronium bromide in patients with moderate to severe airflow limitation.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1001
• Est. completion date: February 2014
• Est. primary completion date: February 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years and older

Eligibility

Inclusion Criteria:

• Male and female patients that have signed informed consent and are >/= 40 years of age.

• Patients with stable COPD according to GOLD 2011.

• Patients with a post-bronchodilator FEV1 of >/= 30% and < 80% predicted and a post-bronchodilator FEV1/FVC <0.70.

• Current or ex-smokers who have a smoking history of at least 10 pack years.

• Patients with an mMRC grade 2 or greater.

Exclusion Criteria:

• Patients with Type I or uncontrolled Type II diabetes - Patients with a history of long QT syndrome or whose QTc measured at Visit 101 (Fridericia method) is prolonged (>450 ms for males and females) and confirmed by a central assessor. (These patients should not be re-screened.)

• Patients who have a clinically significant ECG abnormality at Visit 101 or Visit 102. (These patients should not be re-screened.)

• Patients with a history of malignancy of any organ system, treated or untreated, within the last five years.

• Patients with narrow-angle glaucoma, BPH or bladder-neck obstruction or moderate-severe renal impairment or urinary retention.

• Patients who had a COPD exacerbation within 6 weeks prior to screening.

• Patients who have a respiratory tract infection within 4 weeks prior to screening.

• Patients requiring long term oxygen therapy prescribed for more than 12 hr per day.

• Patients with a history of asthma. 8. Patients with an onset of respiratory symptoms, including COPD diagnosis, prior to age 40 years.

• Patients with a blood eosinophil count of greater than 600 mm/3 during run-in.

• Patients with concomitant pulmonary disease.

• Patients with a diagnosis of alpha-1 anti-trypsin deficiency.

• Patients with active pulmonary tuberculosis.

• Patients in the active phase of a pulmonary rehabilitation programme.

• Other protocol-defined inclusion/exclusion criteria may apply

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Obstructive Pulmonary Disease (COPD)
• Lung Diseases, Obstructive
• Pulmonary Disease, Chronic Obstructive

Intervention

Drug:
• QVA149
QVA149 was supplied in a capsule form in blister packs for use in the Novartis Concept1 SDDPI
• QAB149
QAB149 was supplied in capsule form in blister packs for use in the Novartis Concept1 SDDPI.
• NVA237
NVA237 was supplied in capsule form in blister packs for use in the Novartis Concept1 SDDPI.
• Placebo
Placebo was supplied in capsule form in blister packs for use in the Novartis Concept1 SDDPI.

Locations

Country	Name	City	State
Colombia	Novartis Investigative Site	Armenia
Colombia	Novartis Investigative Site	Barranquilla
Colombia	Novartis Investigative Site	Barranquilla	Atlantico
Egypt	Novartis Investigative Site	Alexandria
France	Novartis Investigative Site	Beuvry
France	Novartis Investigative Site	Nantes
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Reims
Guatemala	Novartis Investigative Site	Guatemala City
Guatemala	Novartis Investigative Site	Guatemala City
Guatemala	Novartis Investigative Site	Guatemala City
Hungary	Novartis Investigative Site	Balassagyarmat
Hungary	Novartis Investigative Site	Debrecen
Hungary	Novartis Investigative Site	Deszk
Hungary	Novartis Investigative Site	Godollo
Hungary	Novartis Investigative Site	Gyor
Hungary	Novartis Investigative Site	Komarom
Hungary	Novartis Investigative Site	Mako
Hungary	Novartis Investigative Site	Miskolc
Hungary	Novartis Investigative Site	Szazhalombatta
Hungary	Novartis Investigative Site	Szombathely
Hungary	Novartis Investigative Site	Tatabanya
Panama	Novartis Investigative Site	Panama City	Panamá
Slovakia	Novartis Investigative Site	Bardejov	Slovak Republic
Slovakia	Novartis Investigative Site	Bojnice	Slovak Republic
Slovakia	Novartis Investigative Site	Galanta
Slovakia	Novartis Investigative Site	Humenne	Slovak Republic
Slovakia	Novartis Investigative Site	Kosice
Slovakia	Novartis Investigative Site	Kosice
Slovakia	Novartis Investigative Site	Kralovsky Chlmec
Slovakia	Novartis Investigative Site	Liptovsky Hradok	Slovak Republic
Slovakia	Novartis Investigative Site	Martin
Slovakia	Novartis Investigative Site	Nitra	Slovak Republic
Slovakia	Novartis Investigative Site	Presov
Slovakia	Novartis Investigative Site	Prievidza
Slovakia	Novartis Investigative Site	Spisská Nová Ves
Slovakia	Novartis Investigative Site	Vrable	Slovak Republic
Slovakia	Novartis Investigative Site	Zvolen
Slovenia	Novartis Investigative Site	Golnik
United States	Novartis Investigative Site	*See Various Dept.'s*	Arizona
United States	Novartis Investigative Site	Arlington	Texas
United States	Novartis Investigative Site	Brandon	New Jersey
United States	Novartis Investigative Site	Buena Park	California
United States	Novartis Investigative Site	Charleston	South Carolina
United States	Novartis Investigative Site	Charleston	South Carolina
United States	Novartis Investigative Site	Charlotte	North Carolina
United States	Novartis Investigative Site	Clearwater	Florida
United States	Novartis Investigative Site	Clearwater	Florida
United States	Novartis Investigative Site	Columbia	South Carolina
United States	Novartis Investigative Site	Corsicana	Texas
United States	Novartis Investigative Site	Dallas	Texas
United States	Novartis Investigative Site	Dallas	Texas
United States	Novartis Investigative Site	Deland	Florida
United States	Novartis Investigative Site	Easley	South Carolina
United States	Novartis Investigative Site	Fort Worth	Texas
United States	Novartis Investigative Site	Ft. Lauderdale	Florida
United States	Novartis Investigative Site	Ft. Worth	Texas
United States	Novartis Investigative Site	Fullerton	California
United States	Novartis Investigative Site	Gaffney	South Carolina
United States	Novartis Investigative Site	Greenville	South Carolina
United States	Novartis Investigative Site	Henderson	Nevada
United States	Novartis Investigative Site	Huntersville	North Carolina
United States	Novartis Investigative Site	Huntsville	Alabama
United States	Novartis Investigative Site	Johnson City	Tennessee
United States	Novartis Investigative Site	Las Vegas	Nevada
United States	Novartis Investigative Site	Lawrenceville	Georgia
United States	Novartis Investigative Site	Lufkin	Texas
United States	Novartis Investigative Site	McKinney	Texas
United States	Novartis Investigative Site	Miami	Florida
United States	Novartis Investigative Site	Miami	Florida
United States	Novartis Investigative Site	Opelousas	Louisiana
United States	Novartis Investigative Site	Orlando	Florida
United States	Novartis Investigative Site	Palmdale	California
United States	Novartis Investigative Site	Pelzer	South Carolina
United States	Novartis Investigative Site	Pensacola	Florida
United States	Novartis Investigative Site	Pensacola	Florida
United States	Novartis Investigative Site	Port Orange	Florida
United States	Novartis Investigative Site	Raleigh	North Carolina
United States	Novartis Investigative Site	Reno	Nevada
United States	Novartis Investigative Site	Riverside	California
United States	Novartis Investigative Site	Rock Hll	South Carolina
United States	Novartis Investigative Site	San Diego	California
United States	Novartis Investigative Site	Sarasota	Florida
United States	Novartis Investigative Site	Seneca	South Carolina
United States	Novartis Investigative Site	Sepulveda	California
United States	Novartis Investigative Site	Shelby	North Carolina
United States	Novartis Investigative Site	Shelby	North Carolina
United States	Novartis Investigative Site	Simpsonville	South Carolina
United States	Novartis Investigative Site	Spartanburg	South Carolina
United States	Novartis Investigative Site	Tamarac	Florida
United States	Novartis Investigative Site	Tampa	Florida
United States	Novartis Investigative Site	Tempe	Arizona
United States	Novartis Investigative Site	Tyler	Texas
United States	Novartis Investigative Site	Union	South Carolina
United States	Novartis Investigative Site	Winter Park	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Colombia,  Egypt,  France,  Guatemala,  Hungary,  Panama,  Slovakia,  Slovenia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Primary: Change From Baseline in Standardized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC) (0-12 Hours (h))	Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FEV1 measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, region, baseline FEV1 * visit interaction, and visit, treatment * visit interaction. Missing values of FEV1 AUC0-12 at Day 1 and Week 12 will not imputed. The trapezoidal rule was used to calculate FEV1 AUC and then normalized to the length of time.	baseline (BL), 12 weeks	No
Secondary	Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Total Score	Participants reported change in health status by using the SGRQ. The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: Part I covers "Symptoms" and is concerned with respiratory symptoms, their frequency and severity; Part II covers "Activity" and is concerned with activities that cause or are limited by breathlessness; Part II is also concerned with "Impacts", which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score was calculated for each of these 3 subscales and a "Total" score was calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status. Missing week 12 data were imputed with Last Observation Carried Forward (LOCF) method but only if measured at day >= 29. A negative change from baseline indicates improvement.	BL, 12 Weeks	No
Secondary	Percentage of Participants With a Clinically Important Improvement of at Least 4 Units in the SGRQ Total Score	Participants reported change in health status by using the SGRQ. The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: Part I covers "Symptoms" and is concerned with respiratory symptoms, their frequency and severity; Part II covers "Activity" and is concerned with activities that cause or are limited by breathlessness; Part II is also concerned with "Impacts", which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score was calculated for each of these 3 subscales and a "Total" score was calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status.	12 weeks	No
Secondary	Change From Baseline in Trough FEV1	Pulmonary function assessments were performed using centralized spirometry according to international standards. Trough FEV1 was analyzed using the same MMRM as specified for FEV1. Trough FEV1 was defined as the mean of FEV1 at 23 h 15 min and 23 h 45 min after the morning dose of the previous day. Before the mean was calculated, a time window of 10 - 13 hours post-evening dose was applied to these 2 measurements. Recordings outside the time window were set to missing.	BL, day 2, day 86	No
Secondary	Change From Baseline in Pre-dose Trough FEV1	Pulmonary function assessments were performed using centralized spirometry according to international standards. Pre-dose trough FEV1 was analyzed using the same MMRM as specified for FEV1. Pre-dose trough FEV1 was defined as the mean of FEV1 at -45 min and -15 min before the morning dose. Since the time of evening dose of the previous day was not recorded at these visits, no time window was applied.	BL, day 85	No
Secondary	Change From Baseline in FEV1	Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FEV1 measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, region, baseline FEV1 * visit interaction, and visit, treatment * visit interaction.	BL, Day 1: 5min, 15min, 1h, 2h, 4h, 6h, 8h, 11h55 min; Day 2: 23h15min, 23h45min; Day 15: -45min, -15min, 1h; Day 29: -45 min, -15min, 1h; Day 57: -45min, -15min, 1h; day 85: -45min, -15min, 5min, 15min, 1h, 2h, 4h, 6h, 8h, 11h; day 86: 23h15min; 23h45min	No
Secondary	Change From Baseline in FVC	Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FVC was defined as the average of the pre-dose FVC measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FVC measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, region, baseline FEV1 * visit interaction, and visit, treatment * visit interaction.	BL, Day 1: 5min, 15min, 1h, 2h, 4h, 6h, 8h, 11h55 min; Day 2: 23h15min, 23h45min; Day 15: -45min, -15min, 1h; Day 29: -45 min, -15min, 1h; Day 57: -45min, -15min, 1h; day 85: -45min, -15min, 5min, 15min, 1h, 2h, 4h, 6h, 8h, 11h; day 86: 23h15min; 23h45min	No
Secondary	Secondary: Change From Baseline in Standardized FEV1 AUC (0-4 h), FEV1 AUC (4-8h), FEV1 AUC (8-12h) and FEV1 AUC (0-12 h)	Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FEV1 measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, region, baseline FEV1 * visit interaction, and visit, treatment * visit interaction. The trapezoidal rule was used to calculate FEV1 AUC and then normalized to the length of time.	BL, day 1, 12 weeks	No
Secondary	Transitional Dyspnea Index (TDI) Focal Score	The Baseline Dyspnea Index (BDI) / TDI is an instrument used to assess a participant's level of dyspnea. The BDI and TDI each have three domains: functional impairment, magnitude of task and magnitude of effort. BDI domains were rated from 0 (severe) to 4 (unimpaired) and rates summed for baseline focal score ranged from 0 to 12; lower scores mean worse severity. TDI domains were rated from -3 (major deterioration) to 3 (major improvement) and rates summed for transition focal score ranged from -9 to 9; negative scores indicate deterioration. A TDI focal score of =1 was defined as a clinically important improvement from baseline.	BL, 12 weeks	No
Secondary	Secondary: Change From Baseline in Mean Daily Number of Puffs of Rescue Medication	Participants completed an electronic diary (eDiary) twice daily at the same time in the morning and evening to record the number of puffs of rescue medication taken in the previous 12 hours. A negative change from baseline indicates improvement.	BL, 12 weeks	No
Secondary	Secondary: Change From Baseline in Mean Total Daily Symptom Score, Mean Daytime Total Symptom Score and Mean Nighttime Total Symptom Score	The participant recorded symptom scores twice daily in the eDiary. The daily clinical symptoms included: cough, wheezing, shortness of breath, sputum volume, sputum color, and night time awakening. The range of scores for each assessment is 0 to 3 where 0 indications No symptom and 3 indicates a Severe symptom. The maximum daytime total score is 27 and the maximum nighttime total score is 27. The total daily symptom score is obtained by adding the scores for the morning and evening symptoms for each day. The maximum possible total daily score is 54. A negative change from baseline indicated improvement.	BL, 12 weeks	No